Transition-metal catalyzed synthesis of Ketoprofen

Abstract

Reações catalisadas por complexos de metais de transição tais como carbonilação, hidrovinilação e hidrogenação foram empregadas na síntese do ácido α-(3-benzoilfenil)propanóico (Cetoprofeno). Acoplamento do tipo Heck entre 3-bromobenzofenona e etileno conduziu à 3-vinilbenzofenona que na sequência, por carbonilação catalisada por paládio, foi tranformada no α-(3benzoilfenil)propanoato de isopropila com rendimento de 95% e regiosseletividade >99,5%. Hidrólise deste éster conduziu ao Cetoprofeno com 90% de rendimento. Cetoprofeno foi também obtido em duas etapas a partir da 3-vinilbenzofenona via reação de hidrovinilação catalisada por níquel que conduz seletivamente ao 3-(3'-benzoilfenil)-1-buteno (96%), seguido por oxidação desta olefina em ácido. A 3-etenilbenzofenona pôde ser sintetizada a partir da 3-bromobenzofenona via uma reação de acoplamento catalisada por paládio. Este alcino foi carabonilado em presença de paládio conduzindo regiosseletivamente (97%) ao α-(3-benzoilfenil)acrilato de metila. A hidrólise do éster conduz ao ácido α-(3-benzoilfenil)acrílico que foi então hidrogenado enantiosseletivamente ao (S)-Cetoprofeno (95% e.e.) usando um complexo Ru-(S)-BINAP como catalisador. Transition metal-catalyzed reactions including carbonylations, hydrovinylations and hydrogenations have been applied in the synthesis of α-(3-benzoylphenyl)propanoic acid (Ketoprofen). 3-Vinylbenzophenone was obtained from 3-bromobenzophenone by a Pd-catalyzed Heck coupling reaction. Pd-catalyzed carbonylation of this olefin gave the isopropyl α-(3-benzoylphenyl) propionate in high yield (95%) and with high regioselectivity (>99.5%). Ketoprofen was obtained in 90% yield by hydrolysis of the isopropyl ester. It was also obtained in two steps from 3vinylbenzophenone by a Ni-catalyzed hydrovinylation selectively affording 3-(3'-benzoylphenyl)-1-butene, followed by an oxidation. 3-Ethynylbenzophenone was obtained from 3bromobenzophenone by Pd-catalyzed coupling reaction. By means of a Pd-catalyzed carbonylation, this alkyne was converted regioselectively (97%) into methyl α-(3-benzoylphenyl) acrylate (93% yield). Hydrolysis of the ester afforded the α-(3-benzoylphenyl)acrylic acid. Asymmetric hydrogenation of this acid to give (S)-ketoprofen in 95% optical yield was achieved using a chiral Ru-(S)-BINAP catalyst.

Pd-catalyzed carbonylation of α-arylvinyl bromides: Synthesis of 2-arylacrylic esters

“…No conversion was observed in the absence of palladium compounds or in the presence of palladium compounds without phosphine ligand. Among the phosphine ligands examined (PPh 3 , PCy 3 , P(o-tol) 3 , dppe, dppp, xantaphos, binap) triphenylphosphine gave the best results in terms of conversion and selectivity. As observed for the synthesis of the unsaturated precursor to Naproxen TM [33] PdCl 2 (PPh 3 ) 2 , an air-stable and easy to make complex, showed to be an excellent catalyst precursor for the carbonylation reaction.…”

“…PdCl(PPh 3 ) 2 [35] and pisobutylstyrene [36] were synthesized as described in the literature. 3-Vinylbenzophenone and 6-methoxy-2-vinyl-naphthalene were obtained form the coupling of the corresponding aryl bromides with ethylene under Heck conditions [3,37]. The (1,2-dibromomoethyl)arenes were obtained in high yields (89-100%) by bromination of the substituted styrenes at 0 • C using CCl 4 as solvent [38].…”

“…Pd-Catalyzed carbonylation reactions provide highly promising and eco-friendly routes for the synthesis of non-steroidal anti-inflammatory profen drugs [1][2][3]. The latter have as the common structural feature a 2-aryl-substituted propionic acid and they have been obtained in acid or ester forms by the hydroxy-or alkoxycarbonylation of vinyl aromatics [4][5][6][7][8][9][10][11][12][13][14], halides [15][16][17][18] and alcohols [19][20][21].…”

“…This process employs three steps instead of the five in the original Boots process, with 100% atom-efficiency, where the key-step is the Pdcatalyzed carbonylation of 1-(p-isobutyphenyl)-ethanol [23]. On the other hand, Pd-catalyzed carbonylations of aryl acetylenes have been also used for the synthesis of 2-arylacrylic acids or esters [1][2][3][24][25][26][27][28][29]. These compounds are useful precursors for the enantioselective synthesis of 2-arylpropionic acids.…”

Palladium‐Catalyzed Carbonylation Reactions of Alkenes and Alkynes

“…[41] In 2006, the procedure devised by Cole-Hamilton [37] and co-workers was applied to convert renewable natural oils into potentially high value terminal esters by a one-pot metathesis-isomerizationmethoxycarbonylation-transesterification reaction sequence. [34] Scheme 7. [43] Vinyl arenes [39e, 44] as well as vinyl acetate [44b, 45] lead predominantly to branched-chain products, as a result of the increased thermodynamic stability of the branched metal complex.…”